CN106883169A - A kind of preparation method and applications of 3 (naphthyl of 4 cyano group 1) 4 haloperidids - Google Patents
A kind of preparation method and applications of 3 (naphthyl of 4 cyano group 1) 4 haloperidids Download PDFInfo
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- CN106883169A CN106883169A CN201710214917.5A CN201710214917A CN106883169A CN 106883169 A CN106883169 A CN 106883169A CN 201710214917 A CN201710214917 A CN 201710214917A CN 106883169 A CN106883169 A CN 106883169A
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- compound
- haloperidids
- cyano group
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- naphthyl
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- 0 *c1ccccc1-c(c1c2cccc1)ccc2C#N Chemical compound *c1ccccc1-c(c1c2cccc1)ccc2C#N 0.000 description 3
- SAGLLWRILHGWGB-UHFFFAOYSA-N Cc1ccncc1-c(c1c2cccc1)ccc2C#N Chemical compound Cc1ccncc1-c(c1c2cccc1)ccc2C#N SAGLLWRILHGWGB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
Abstract
The present invention relates to pharmaceutical chemistry synthesis field, and in particular to a kind of preparation method and applications of 3 (naphthyl of 4 cyano group 1) 4 haloperidids.It is an object of the present invention to provide a kind of synthetic method of 3 (naphthyl of 4 cyano group 1) 4 haloperidids (compound 3), specially compound 1 carries out coupling reaction prepare compound 3 after diazotising with compound 2：
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis field, and in particular to a kind of 3- (4- cyano group -1- naphthyls) -4- haloperidids
Preparation method and applications.
Background technology
Gout is purine substance metabolic disorder, and the purine of the generation such as people's nucleic acid in vivo oxidation Decomposition and exogenous intake increases
Plus after, a large amount of uric acid can be further produced in liver, the synthesis of uric acid increases or discharge is reduced, and causes hyperuricemia, blood urine
Acid concentration persistently increases causes urate crystal to deposit soft tissue, causes tissue foreign matter inflammatory reaction, i.e. gout.Its morbidity premise
It is hyperuricemia, clinical signs are hyperuricemia, gouty acute arthritis, tophaceous deposition, the chronic pass of characteristic
Section inflammation and arthritis deformans, often involve kidney, trigger arteriosclerotic kidney and kidney calculus urate.At present, the incidence of disease of gout is being just
Increasing sharply, gradually developing into after the 4th kind of metabolic disease after hypertension, high fat of blood and hyperglycaemia.
The clinical treatment of gout with colchicin, non-steroid anti-inflammatory drug, hormone, promote uric acid excretion medicine (such as probenecid,
Sulfinpyrazone and Benzbromarone) and suppress based on uric acid synthetic drug (allopurinol).Acute period of disease is mainly using colchicin, non-
Steroidal anti-inflammatory drugses (anodyne), hormone, mainly application promoted uric acid excretion medicine, suppressed uric acid synthetic drug the paracmasis.Wherein, the autumn
Tazettine is close due to its effective dose and toxic dose, and adverse reaction is more, therefore should be careful when using；About 2% trouble
Person has allergic symptom to allopurinol, and clinical manifestation is heating, fash, itch etc., once there are these symptoms, should be stopped immediately
Medicine, and give desensitization treatment；Additionally, probenecid etc. promotes the medicine of uric acid excretion while uric acid excretion is promoted, can cause
Urate crystals are deposited in urinary tract, trigger renal colic and kidney function damage.In general, the medicine of gout still species compared with
It is few, limited amount, and many adverse drug reactions are more, bioavilability is low, poor resistance, therefore find efficient, toxic and side effect
Medicine small, that blocking gout occurs from source has been current research emphasis.
AstraZeneca (AstraZeneca) and its subsidiary Ya De are biochemical (Ardea Biosciences Inc) in recent years
The first generation lithate transporter 1 (URAT1) inhibitor RDEA594 is have developed, and carries out structure optimization on this basis and be
The new compound of row, with RDEA3170 as representative, the selectivity of its drug effect and URAT1 is superior to RDEA594, in treatment gout side
Face has bigger potentiality.Research finds that inhibitory action of the RDEA3170 in vitro to URAT1 transhipment uric acid is the 3 of Benzbromarone
Times, be 100 times of Sulfinpyrazone and probenecid.
The synthetic method of various RDEA3170 classes compounds is disclosed in existing document, wherein compound shown in formula 3 is it
Crucial intermediate, structural formula is as follows：
The synthetic route on compound 3 is disclosed in patent US20130281469A1, with the bromo- 4- chloropyridines of 3- and 4-
Cyano group naphthalene boronic acids prepare compound 3 for raw material through suzuki reaction (i.e. Suzuki coupling reactions)：
In above-mentioned route the raw materials used extremely difficult acquisition of 4- cyano group naphthalene boronic acids, Zhang Xiansheng etc. document (《Modern medicines with face
Bed》, volume 30, the 10th phase, in October, 2015, page 1179 page -1184) in report the synthetic method on the raw material, pass through
The reaction of Isosorbide-5-Nitrae-dibromine naphthalene and cuprous cyanide prepares the bromo- 1- naphthonitriles of 4-, the bromo- 1- naphthonitriles of 4- under butyl lithium effect with borate
Reaction is so as to obtain 4- cyano group naphthalene boronic acids.Due in Isosorbide-5-Nitrae-dibromine naphthalene two bromines it is active identical, byproduct of reaction is more, separates tired
It is difficult；Additionally, using highly toxic cuprous cyanide reagent in reaction, it is unfavorable for safety in production, is not suitable for industrialization.
In view of the medical value of RDEA3170, finds a 3- (4- that are safe and simple, easy to operate, being adapted to industrialized production
Cyano group -1- naphthyls) preparation method of -4- haloperidids is necessary.
The content of the invention
In order to solve drawbacks described above present in prior art, the present invention provides a kind of safe and simple, easy to operate, suitable
The preparation method of 3- (4- cyano group -1- naphthyls) -4- haloperidids of industrialized production.
It is an object of the present invention to provide a kind of synthesis of 3- (4- cyano group -1- naphthyls) -4- haloperidids (compound 3)
Method, specially compound 1 carry out coupling reaction prepare compound 3 after diazotising with compound 2：
Wherein, X represents halogen；Preferably, X represents bromine or chlorine.
The molar equivalent of the compound 1 and compound 2 is than preferably 1.2-2.0:1.0, more preferably 1.5:1.0；
The diazotising is carried out in nitrous acid ester and nitrite or in the presence of strong acid and nitrite；
The nitrous acid ester is including isoamyl nitrite, nitrous acid tert-pentyl ester, nitrite tert-butyl, Isopropyl Nitrite etc.
Alkyl nitrite；Preferably, the nitrous acid ester is isoamyl nitrite or nitrite tert-butyl.
The nitrite includes the conventional alkali metal salt such as natrium nitrosum, potassium nitrite.
The strong acid includes the conventional inorganic acid such as hydrochloric acid, sulfuric acid.
The diazotising can be completed with coupling reaction by single step reaction.
The coupling reaction is carried out in polar non-solute, and the polar non-solute includes dimethyl sulfoxide (DMSO)
(DMSO), the conventional organic solvent such as N,N-dimethylformamide (DMF), toluene, acetonitrile, dichloromethane；The aprotic, polar
Solvent is preferably DMSO.
Further, the diazotising is carried out in the presence of nitrous acid ester and nitrite, and reaction temperature is 30 DEG C -50
℃；Or, the diazotising in the presence of strong acid and nitrite, while in the effect of fluoboric acid (preferred concentration is 48%)
Under carry out, the diazo-reaction temperature be -20 DEG C -5 DEG C.
It is a further object to provide a kind of application of the compound 3 in RDEA3170 is synthesized, specifically include
Compound 3 obtains compound 4 through sulfhydrylation, and compound 4 obtains compound 5 with the reaction of alkyl halide base ester, and the hydrolysis of compound 5 is obtained
Compound 6：
Wherein, X represents halogen, R1Represent C1-6 alkyl, R2、R3Hydrogen or C1-6 alkyl are represented respectively；Preferably, X is represented
Bromine or chlorine, R1、R2、R3Represent methyl.
The mercaptolation is carried out at being 90-120 DEG C in temperature；
The hydrolysis is carried out in highly basic, and the highly basic is the alkali metal hydroxides such as NaOH, potassium hydroxide.
The present invention provides a kind of synthetic method of new 3- (4- cyano group -1- naphthyls) -4- haloperidids, and the method is with 3- ammonia
Base -4- haloperidids and 1- naphthonitriles are raw material, and raw materials used and reagent is cheap and easy to get, react safe, simple to operate, are adapted to
Industrialized production；The present invention also provides a kind of 3- (4- cyano group -1- naphthyls) -4- haloperidids and is preparing URAT1 class medicines simultaneously
In application.
Specific embodiment
With reference to specific embodiment, the invention will be further described, it should be appreciated that following examples are merely to illustrate this
Invent rather than limit the scope of the invention.
Method used unless otherwise specified, is conventional method in the following example.Material needed for following examples
Material or reagent, are market and buy unless otherwise specified.Wherein, involved concentration is mass concentration unless otherwise specified.
Embodiment 1：
To sequentially adding compound 1-1 (5g, 0.039mol), compound 2 (4.0g, 0.026mol), nitrous in reaction bulb
Isoamyl valerate (6.0g, 0.052mol), natrium nitrosum (1.8g, 0.026mol), 20mL DMSO are passed through nitrogen, are heated to 40 DEG C
Reaction 30min, recovers room temperature complete to reaction.Reaction solution is poured into separatory funnel, 100mL water is added, with 100mL acetic acid second
Ester is extracted, collected organic layer, anhydrous sodium sulfate drying, removes solvent, and (eluent gradient is column chromatography for separation, petroleum ether:Acetic acid
Ethyl ester=5:1、3:1、1:1) white solid 2.3g, is obtained, yield is 34%.
Embodiment 2：
Compound 1-1 (12.8g, 0.1mol), concentrated hydrochloric acid (25mL, 0.3mol), temperature are added in the there-necked flask of 500mL
- 10 DEG C of stirrings are down to, 30% sodium nitrite in aqueous solution (34.5mL, 0.15mol) is added dropwise, rate of addition is with the oxygen of brown of not emerging
Change carbon gas, completion of dropping continues to stir 30min, has solid to separate out, and Weigh Compound 2 (7.6g, 0.05mol) is dissolved in 5mL bis-
In chloromethanes, it is slowly added dropwise into reaction bulb, recovers to being stirred at room temperature.TLC (thin-layer chromatographic analysis) monitoring reactions, reaction is complete
Afterwards, reaction solution is poured into separatory funnel, adds 80mL water, the extraction of 100mL dichloromethane, collected organic layer, anhydrous sodium sulfate
Dry, remove solvent, (eluent gradient is crude product, petroleum ether through column chromatography for separation:Ethyl acetate=5:1、3:1、1:1), obtain
White solid 3.4g, yield is 26%.
Embodiment 3：
Addition compound 1-1 (12.8g, 0.1mol) in the there-necked flask of 500mL, 48% fluoborate aqueous solution (54.8mL,
0.3mol), 6mol/L aqueous hydrochloric acid solutions (33mL, 0.2mol), temperature is down to -10 DEG C of stirrings, and 30% sodium nitrite solution is added dropwise
(34.5mL, 0.15mol), rate of addition continues to stir 30min with the carbon oxide gas of brown of not emerging, completion of dropping, there is solid
Body is separated out.Filtering, filter cake is added in the DMSO solution (80mL) of compound 2 (7.6g, 0.05mol), is stirred at room temperature.TLC is monitored
Reaction, after reaction completely, reaction solution is poured into separatory funnel, adds 80mL water, and the extraction of 100mL ethyl acetate is collected organic
Layer, anhydrous sodium sulfate drying removes solvent, and through column chromatography for separation, (eluent gradient is crude product, petroleum ether:Ethyl acetate=5:
1、3:1、1:1) white solid 3.8g, is obtained, yield is 29%.
Embodiment 4：
It is 1 equivalent with the consumption of compound 2 according to the method prepare compound 3-1 of embodiment 1, is separately added into different
Nitrous acid ester, the consumption of adjustment compound 1-1 and reaction temperature, and real-time monitoring response situation, result of study such as following table institute
Show：
As can be seen from the above table, the too low raw material reaction of reaction temperature is not complete, the too high easy generation side reaction of reaction temperature, both
All causing reaction yield reduces.
Embodiment 5：
To in 500mL there-necked flasks add compound 3 (9.2g, 0.035mol), nine water vulcanized sodium (25.2,0.105mol) and
100mLDMF, mixture 100 DEG C of heating stirring reaction 2h, TLC monitoring reactions under a nitrogen of gained, after reaction completely, will be cold
But the reaction solution after is poured into separatory funnel, adds 80mL water, is extracted twice with dichloromethane (100mL*2), collects water layer, is used
Concentrated hydrochloric acid aqueous solution adjusts pH to 5-6, obtains slurry, and 1h is stirred at room temperature, and solid is collected by filtration, and is vacuum dried at 45 DEG C, obtains
6.9g compounds 4, yield is 76%.
To compound 4 (10.5g, 0.04mol) is added in 500mL there-necked flasks, 100mL DMF stirring and dissolvings are added, added
Solid carbonic acid potassium (16.56g, 0.12mmol) and 2 bromo 2 methyl propionic acid methyl esters (8.7g, 0.048mmol), stir anti-at room temperature
5h is answered, TLC monitoring reactions after reaction completely, reaction solution are poured into separatory funnel, add water (100mL), ethyl acetate
(150mL) is extracted, collected organic layer, anhydrous sodium sulfate drying, removes solvent, obtains 13.6g compounds 5 (colourless oil liquid),
Yield is 94%.
To sequentially adding compound 5 (7.2g, 0.02mol), 50mL methyl alcohol water dissolves, 10% hydrogen-oxygen in 250mL there-necked flasks
Change sodium (40mL, 0.1mol) aqueous solution, be heated to backflow, react 2h, TLC monitoring reactions, after reaction completely, in condition of ice bath
Under, it is slow that 2mol/L aqueous hydrochloric acid solutions regulation pH=6-7 is added dropwise, there is white solid to separate out, filter, filter cake vacuum at 45 DEG C
Dry, obtain white solid 6.0g, yield is 86%.
Claims (10)
1. the synthetic method of 3- shown in a kind of formula 3 (4- cyano group -1- naphthyls) -4- haloperidids, it is characterised in that methods described is
There is coupling reaction with compound 2 after diazotising and compound 3 be obtained in compound 1：
Wherein, X represents halogen.
2. method according to claim 1, it is characterised in that the compound 1 is with the molar equivalent ratio of compound 2
1.2-2.0:1.0。
3. method according to claim 2, it is characterised in that the diazotising is under nitrous acid ester and nitrite effect
Carry out.
4. method according to claim 3, it is characterised in that the temperature of the coupling reaction is 30 DEG C -50 DEG C.
5. method according to claim 1, it is characterised in that the diazotising is entered in the case where nitrite and strong acid are participated in
OK.
6. method according to claim 5, it is characterised in that the diazotising is carried out in the presence of fluoboric acid simultaneously.
7. method according to claim 6, it is characterised in that the diazotizing temperature is -20 DEG C -5 DEG C.
8. the method according to claim 1-7, it is characterised in that the coupling reaction is entered in polar non-solute
OK.
9. method according to claim 8, it is characterised in that the diazotising and coupling reaction are complete by single step reaction
Into.
10. application of the compound 3 obtained in claim 1-9 methods describeds in RDEA3170 synthesis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710214917.5A CN106883169A (en) | 2017-04-01 | 2017-04-01 | A kind of preparation method and applications of 3 (naphthyl of 4 cyano group 1) 4 haloperidids |
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| CN201710214917.5A CN106883169A (en) | 2017-04-01 | 2017-04-01 | A kind of preparation method and applications of 3 (naphthyl of 4 cyano group 1) 4 haloperidids |
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| CN106883169A true CN106883169A (en) | 2017-06-23 |
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| CN201710214917.5A Pending CN106883169A (en) | 2017-04-01 | 2017-04-01 | A kind of preparation method and applications of 3 (naphthyl of 4 cyano group 1) 4 haloperidids |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103068801A (en) * | 2010-06-16 | 2013-04-24 | 亚德生化公司 | Thioacetate compounds, compositions and methods of use |
-
2017
- 2017-04-01 CN CN201710214917.5A patent/CN106883169A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103068801A (en) * | 2010-06-16 | 2013-04-24 | 亚德生化公司 | Thioacetate compounds, compositions and methods of use |
Non-Patent Citations (1)
| Title |
|---|
| HASSANALY, PARINA ET AL.: "Attempt to synthesize nitrogenous aza-aromatic heterocycles by radical substitution. Effect of primary aromatic heterocyclic amines of alkyl nitrites in an acidic medium", 《BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE》 * |
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Application publication date: 20170623 |